Stroke is a leading cause of mortality and disability, with several thousands of individuals being affected every year in the United States. Some degree of spontaneous behavioral recovery occurs during the weeks to months after stroke. It is believed that reorganization of surviving brain regions is a contributing factor to this improvement. As support for this hypothesis, enhancements in behavioral performance are correlated with plasticity of remaining intact cortex (peri-infarct cortex) in animal models of cortical stroke. Synaptogenesis and angiogenesis that occur in this region seem likely to contribute to improved functional outcome following injury. Since improved functional outcome is further facilitated by skilled behavioral training, it seems likely that training influences these neuroanatomical changes in peri-infarct cortex. The central hypothesis of this proposal is that spontaneous and training-induced vascular and dendritic plasticity support behavioral recovery following ischemic insult. This will be investigated using in vivo imaging in a mouse model of upper extremity impairment after cortical stroke. While both dendritic and vascular plasticity have been observed following ischemic lesions, the coordination between the two and the role they may play in behavioral outcome has not been explored. To investigate the relationship between behavioral outcome and vascular and dendritic plasticity, we will observe changes in these processes over time with two-photon microscopy (Aim 1) and determine how behavioral training alters these plastic responses (Aim2). We will also assess the functional relevance of vascular plasticity in behavioral outcome following rehabilitation by inhibiting angiogenesis in a subgroup of animals during skilled motor training (Aim 3). For Aim 1, rats will receive unilateral ischemic lesions of the sensorimotor cortex (SMC) and undergo periodic in vivo imaging sessions using two-photon microscopy. Postmortem anatomical analyses will be used to further examine vascular and dendritic plasticity in deeper layers of cortex. Skilled motor training of the paretic limb can further enhance functional recovery, while training of the nonparetic limb impairs behavioral outcome. However, the anatomical substrates of these phenomena are not well understood. For Aim 2, the same lesion model will be used as in Aim 1, with the addition of animals receiving paretic and nonparetic forelimb motor training (skilled reaching). Finally, Aim 3 will investigate the effects of pharmacological inhibition of vascular plasticity on functional outcome following rehabilitative training. Using the same lesion model as Aims 1-2, we will determine the importance of vascular plasticity to functional recovery following motor skill rehabilitation. The proposed research will help elucidate neuroanatomical substrates that promote motor recovery following stroke. PUBLIC HEALTH RELEVANCE: The aim of the proposed series of experiments is to understand how vascular remodeling influences and supports functional recovery following stroke, and how behavioral experience further shapes this plastic response. These studies specifically address how injury-induced plasticity and motor skill learning restructure existing neural networks to drive functional recovery. The goal of this work is to obtain a basic understanding of the anatomical and behavioral substrates that may serve as targets for the facilitation and promotion of behavioral recovery following neural insult.